Investigators that constitute a pediatric asthma clinical research network will have an extraordinary opportunity and responsibility to advance the field in the diagnosis, pathogenesis, and treatment of children and adolescents with asthma. This research team should have the courage and insight to be both innovative and aspiring in the development of protocols to address questions currently unanswered due to shortcomings in trial design in previously conducted studies. Clinical trials designed to evaluate a particular form of treatment for childhood asthma need first, to recognize the potential for the intervention to modulate either the initiation of the asthmatic phenotype or the induction of asthma exacerbations once the syndrome has become established; and second, to comprehensively evaluate the short- and long-term consequences of any treatment intervention. Ideally, appropriately designed protocols should provide insight into selecting the right child, to treat at the right time, and with the right medication. To address these needs, we propose two protocols that bookend the extremes of important questions in pediatric asthma in age groups (infancy and adolescence) in which asthma therapy has been incompletely examined. In the first protocol, we propose to evaluate the safety and efficacy of two types of long term controller therapies (an inhaled corticosteroid and a leukotriene receptor antagonist) in children divided into two separate phenotypic groups based on risk factors previously demonstrated to be associated with persistent (asthma) versus transient wheezing. In the second protocol, we propose to evaluate the effects of inhaled corticosteroids during a period of growth and development that many clinicians are concerned about (adolescence), but a time period that has never been critically examined. Although both protocols are challenging, we consider them to be potential examples of the types of comprehensive clinical investigations a pediatric oriented network should be capable of developing and conducting in a way that will provide clinically relevant and useful information, while at the same time establishing and maintaining acceptable standards of safety in these age groups.